In an attempt to approach the problem of the neural bases of learning and memory, we have chosen to ask how small bits of the nervous system, i.e., a local neuron circuit like the hippocampus, can perform associative forms of information storage. For the past 30 years, it has generally been assumed by theoreticians that the brain contains synapses that can modify their synaptic efficacy as a function of the degree of coactivity with other convergent synapses. This type of synapse is called a Hebb synapse. In preliminary investigations, we have discovered in the hippocampal formation of a synapse which possesses the requisite capacities of a Hebb synapse. The experiments of this proposal are designed to find out more about these synapses, asking: What are the rules which govern the specific adjustments of synaptic efficacy of individual synapses? To answer these questions we will use both the methods of neurophysiology and electron microscopy. Using both extracellular and intracellular recording and multiple stimulating electrodes, we will define the nature of the activity that allows a synapse to alter its efficacy. By doing so we hope to better understand the types of changes that can occur in a physiological, functioning system. Both the neurophysiology and electron microscopy will be used to examine the mechanism controlling changes in synaptic efficacy. Two particular distinct hypotheses are that potentiation results from: increases of receptor activation (e.g. more transmitter or more receptors) versus alterations of dendritic spine stem resistances. Extrapolation of the rules for associative modification of synapses leads to experimental predictions for axonal sheding and axonal sprouting with electrical stimulation. Additionally a related series of experiments are proposed to investigate the role of the cytoskeleton in controlling shape, growth, and resorption of the dendritic spine with potentiation and other manipulations.